Articles

Timing of radiotherapy after radical prostatectomy

(RADICALS-RT): a randomised, controlled phase 3 trial
Christopher C Parker, Noel W Clarke, Adrian D Cook, Howard G Kynaston, Peter Meidahl Petersen, Charles Catton, William Cross, John Logue,
Wendy Parulekar, Heather Payne, Rajendra Persad, Holly Pickering, Fred Saad, Juliette Anderson, Amit Bahl, David Bottomley, Klaus Brasso,
Rohit Chahal, Peter W Cooke, Ben Eddy, Stephanie Gibbs, Chee Goh, Sandeep Gujral, Catherine Heath, Alastair Henderson, Ramasamy Jaganathan,
Henrik Jakobsen, Nicholas D James, Subramanian Kanaga Sundaram, Kathryn Lees, Jason Lester, Henriette Lindberg, Julian Money-Kyrle,
Stephen Morris, Joe O’Sullivan, Peter Ostler, Lisa Owen, Prashant Patel, Alvan Pope, Richard Popert, Rakesh Raman, Martin Andreas Røder,
Ian Sayers, Matthew Simms, Jim Wilson, Anjali Zarkar, Mahesh K B Parmar, Matthew R Sydes

Summary
Background The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed Published Online
to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for September 28, 2020
https://doi.org/10.1016/
prostate-specific antigen (PSA) biochemical progression. S0140-6736(20)31553-1
See Online/Comment
Methods We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 https://doi.org/10.1016/
or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after S0140-6736(20)31957-7
radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, Department of Oncology,
and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with Royal Marsden NHS
Foundation Trust, Sutton, UK
salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was
(Prof C C Parker MD); Institute
not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule of Cancer Research, Sutton, UK
(52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant (Prof C C Parker); Department of
metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% Clinical Oncology, Belfast
Health and Social Care Trust,
at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol
Belfast, UK
hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (Prof J O’Sullivan MD);
(HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. Department of Oncology,
University Hospital
Birmingham, Birmingham, UK
Findings Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage (A Zarkar FRCR); Department of
radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years Urology, University Hospitals
(IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy Birmingham NHS Foundation
group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported Trust, Birmingham, UK
(R Jaganathan FRCS,
radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was P Patel FRCS); Department of
85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, Urology, Bradford Teaching
95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the Hospitals NHS Foundation
adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; Trust, Bradford, UK,
(R Chahal FRCS); Department of
p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean Urology, Bristol Urological
score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the Institute, North Bristol
adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). Hospitals, Bristol, UK
(R Persad FRCS); Department of
Oncology, Bristol Cancer
Interpretation These initial results do not support routine administration of adjuvant radiotherapy after radical Institute, University Hospitals
prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage Bristol, Bristol, UK
radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. (Prof A Bahl FRCR); Department
of Clinical Oncology, Kent
Oncology Centre, Canterbury,
Funding Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society. UK (R Raman FRCR);
Department of Urology,
Copyright © 2020 Elsevier Ltd. All rights reserved. East Kent Hospitals University
Foundation Trust, Canterbury,
UK (B Eddy FRCS); Department
Introduction with salvage radiotherapy given later only to those men of Urology, Cardiff University
Radical prostatectomy is a standard treatment for clin­ who develop a rising prostate-specific antigen (PSA) School of Medicine, Cardiff
ically localised prostate cancer, and is often followed by concentration. It is possible that earlier treatment with University, Cardiff, UK,
(Prof H G Kynaston MD);
postoperative radiotherapy to the prostate bed.1,2 The adjuvant radiotherapy might be more effective than a
Department of Oncology
optimal timing of radiotherapy after radical prostatectomy policy of delayed salvage radiotherapy for biochemical (P M Petersen MD) and
remains uncertain. Adjuvant radiotherapy can be given progression. However, the salvage radio­ therapy policy Department of Urology
early, to those with no evidence of residual disease after avoids unnecessary treatment of those cured by surgery (Prof K Brasso PhD,
Prof M A Røder PhD),
surgery, to reduce the risk of subsequent recurrence. alone and can therefore result in less treatment-related
Copenhagen Prostate Cancer
Alternatively, patients might be followed up after surgery, morbidity. Center, Copenhagen University

www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1 1

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Hospital, Rigshospitalet,
Copenhagen, Denmark; Research in context
Department of Oncology, Royal
Surrey County Hospital NHS Evidence before this study Added value of this study
Foundation Trust, Guildford, The trial was developed by an international trial development RADICALS-RT compared adjuvant radiotherapy against a
UK (C Goh MD, group. The evidence before the development of the trial policy of early salvage radiotherapy in the event of prostate-
J Money-Kyrle FRCR);
Department of Oncology
in 2005 was well known to the prostate cancer community specific antigen biochemical progression. Adjuvant
(H Lindberg MD) and from high-profile randomised controlled trials. Previous radiotherapy did not have any benefit in comparison with the
Department of Urology randomised controlled trials of adjuvant radiotherapy after salvage policy, but did increase the risk of urinary and bowel
(H Jakobsen MD), Herlev radical prostatectomy showed a reduced risk of disease morbidity.
University Hospital, Herlev,
Denmark; Department of
recurrence, but conflicting results for longer-term outcomes.
Implications of all the available evidence
Urology, Hillingdon Hospital, These trials are difficult to interpret in the context of current
These results are published in the context of two other trials
Middlesex, UK (A Pope MD); practice due to their late use, if at all, of salvage radiotherapy in
Mount Vernon Hospital, that assessed radiotherapy timing and a prospectively planned
the control group. Clinical guidelines differed in their approach
Northwood, UK (A Pope); meta-analysis, ARTISTIC. In the absence of any reliable
Department of Urology, Hull
to postoperative radiotherapy timing, and surveys of clinical
evidence that adjuvant radiotherapy does more good than
University Hospitals NHS Trust, opinion did not find a consensus on this issue. The evidence
harm, observation with salvage treatment for prostate-specific
Hull, UK (M Simms FRCS); before these results were developed with the ARTISTIC meta-
Department of Oncology, antigen biochemical progression should be the current
analysis group in a systematic review set out in PROSPERO
Canadian Cancer Trials Group, standard of care after radical prostatectomy.
Queen’s University, Kingston, (CRD42019132669), which included searches of trial registers
ON, Canada (W Parulekar MD); and major oncology conference proceedings.
Department of Oncology, Leeds
Cancer Centre (L Owen FRCR)
and Department Of Urology
Previously reported randomised controlled trials of RADICALS-RT was designed to compare the efficacy
(W Cross PhD), St James’s
University Hospital, Leeds, UK; adjuvant radiotherapy after radical prostatectomy have and safety of adjuvant radiotherapy after radical prost­a-
St James’s Institute of shown a reduced risk of early disease recurrence, but tectomy versus a policy of observation with early salvage
Oncology, Leeds, UK have given conflicting results with regard to longer-term radiotherapy for PSA biochemical progression (referred
(D Bottomley FRCR);
outcomes. Although the SWOG 8794 trial3 found an to in the protocol as PSA failure), with a focus on long-
Department of Clinical
Oncology (S Morris FRCR) and overall survival benefit for adjuvant radiotherapy in a term outcome measures. This is the first report from
Department of Urology cohort of 425 patients recruited between 1988 and 1997, RADICALS-RT on early outcome measures, presented
(R Popert MS), Guys Hospital, the EORTC 22911 trial4,5 of 1005 patients recruited with the support of the independent data monitoring
London, UK; Institute of
between 1992 and 2001 did not. Furthermore, these trials committee and the trial steering committee.
Cancer Research, London, UK
(Prof N D James PhD); are of limited relevance to contemporary clinical practice
Department of Oncology, Royal because patients in the respective control groups did not Methods
Marsden NHS Foundation receive timely salvage radiotherapy. Two further trials Study design and participants
Trust, London, UK
(Prof N D James); Department of
of adjuvant radiotherapy, the ARO 96-02 trial6 and the RADICALS is an international, phase 3, multicentre,
Oncology, University College Finnish Radiation Oncology Group trial,7 were not open-label, randomised controlled trial in prostate cancer.
London Hospitals, London, UK designed to report with power on long-term outcomes. The protocol contains two separate randomisations
(Prof H Payne FRCP); Kent Clinical guidelines differ in their approach to post­ with overlapping patient groups and was implemented
Oncology Centre, Maidstone
Hospital, Kent, UK
operative radiotherapy timing. The European Society of at 138 trial-accredited centres in Canada, Denmark,
(K Lees FRCR); Department of Medical Oncology guideline states “immediate post- Ireland, and the UK. Participants were randomly assigned
Urology, Maidstone and operative radiotherapy after radical prostatectomy is shortly after radical prostatectomy to adjuvant or sal­
Tunbridge Wells NHS Trust, not routinely recommended”, whereas the American vage postoper­ative radiotherapy (RADICALS-RT), and, in
Maidstone, UK
(A Henderson FRCS);
Society for Radiation Oncology and American Urological patients plan­ ned for postoperative radiotherapy, to 0
Department of Oncology Association guideline, while stopping short of recom­ versus 6 months versus 24 months of hormone therapy
(J Logue FRCR), Department of mending adjuvant radiotherapy, states “patients should (RADICALS-HD). Here, we report results from the
Oncology, Genito-Urinary be counselled that high-quality evidence indicates that… radiotherapy timing randomisation, RADICALS-RT, com­
Cancer Research Group
(Prof N W Clarke ChM),
adjuvant radiotherapy…reduces the risk of biochemical paring the addition of immediate postoperative radio­
­
Department of Surgery recurrence, local recurrence, and clinical progression”.8 therapy (research) to a salvage postoperative radiotherapy
(Prof N W Clarke), The Christie Not surprisingly, there has been poor consensus policy (control).
Hospital, Manchester, UK; regarding the timing of postoperative radio­therapy.9 A Patients with non-metastatic adenocarcinoma of the
Department of Urology, Salford
Royal Hospitals, Manchester,
survey in 2018 of 88 North American radiation oncologists prostate were eligible for RADICALS-RT if they had
UK (Prof N W Clarke); specialising in prostate cancer found that 55% recom­ undergone radical prostatectomy, had postoperative
Department of Urology, Centre mend an adjuvant radiotherapy policy and 45% rec­ PSA of 0·2 ng/mL or less, and at least one specified risk
Hospitalier de l’Université de
ommend a policy of salvage radiotherapy in the event of factor (ie, pathological T-stage 3 or 4, Gleason score 7–10,
Montreal, Montreal, QC,
Canada (Prof F Saad MD); recurrence.10 At the Advanced Prostate Cancer Consensus posi­tive margins, or preoperative PSA of 10 ng/mL
Department of Urology, Conference 2017, faced with a range of clinical scenarios, or more). Appropriate ethical review was in place for
Anuerin Bevan University up to 48% of the panel voted in favour of adjuvant each partic­ipating country. All participants gave written
Health Board, Newport, UK
radiotherapy.11 informed consent. The protocol is available online.

2 www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1

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Randomisation and masking Outcomes (J Wilson FRCS); Mount Vernon

Participants were randomly assigned, within 22 weeks Patients were seen by a site investigator every 4 months Cancer Centre, Northwood, UK
(P Ostler FRCR, A Pope);
after radical prostatectomy, to receive either adjuvant from randomisation for 2 years, then 6-monthly until Department of Oncology
radiotherapy to the prostate bed with or without pelvis, 5 years, then annually until 15 years. Clinician-reported (S Gibbs FRCR) and Department
or close observation with salvage radiotherapy to the data were collected at each follow-up visit on diarrhoea, of Urology (S Gujral MBBS),
prostate bed with or without pelvis given in the event proctitis, cystitis, haematuria, and urethral stricture, Barking, Havering and
Redbridge University Hospitals
of PSA biochemical progression, defined as either graded according to Radiation Therapy Oncology Group NHS Trust, Romford, UK;
two consecutive rising PSA amounts with a PSA of (RTOG) toxicity score.12 Data for other adverse events Department of Clinical
greater than 0·1 ng/mL, or three consecutive rising PSA were collected if the event met the criteria to be classified Oncology, University Hospital
amounts. Randomisation, using a 1:1 allocation, was as a serious adverse event. Patient-reported data were Southampton, Southampton,
UK (C Heath FRCR); Department
done centrally using mini­ misation with a random col­lected at baseline, 1, 5, and 10 years post-randomisation of Oncology, South West Wales
element, which was stratified by Gleason sum score, with use of standard questionnaires that included Vaizey Cancer Centre, Swansea, UK
margin status, radiotherapy schedule, and study centre. (bowel) and International Continence Society Male (J Lester FRCR); Department of
No masking was used in the trial. Short-Form (urinary incontinence). Radiation Oncology, Princess
Margaret Hospital, University
RADICALS was designed to focus on long-term Health Network, Toronto, ON,
Procedures outcomes, with the primary outcome measure of dis­ Canada (Prof C Catton MD);
Radiotherapy to the prostate bed used a non-randomised ease-specific survival for both the RADICALS-RT and Department of Oncology
(J Anderson FRCR) and
dose-fractionation schedule of either 66·0 Gy in 33 frac­ RADICALS-HD randomisations, and freedom-from-
Department of Urology
tions or 52·5 Gy in 20 fractions. Radiotherapy was deliv­ distant metastases (FFDM) as a key secondary outcome (S Kanaga Sundaram FRCS),
ered once a day with five sessions per week. Treatment measure. Distant metastases could be bone, liver, lung, Mid Yorkshire Hospitals NHS
commenced within both 2 months after randomisation distant node, or other metastases, but did not include Trust, Wakefield, UK;
Department of Oncology
and 26 weeks of radical prostatectomy for patients pelvic nodes. It became apparent after the EORTC 22911
(I Sayers MBBS) and
on adjuvant radiotherapy, and within 2 months of and SWOG 8794 trials were published that patient Department of Urology
PSA biochemical progression for patients on salvage outcomes were better than previously reported.3,5 The (P W Cooke MD), The Royal
radio­therapy. Radio­therapy could be delayed by up to RADICALS team instigated discussions with two Wolverhampton NHS Trust,
Wolverhampton, UK; and MRC
2 months if the patient was also due to receive hormone other then-recruiting trials addressing radiotherapy
Clinical Trials Unit at UCL,
therapy. timing, RAVES13 and GETUG-AFU 17,14 which led to the Institute of Clinical Trials and
Participants could also receive radiotherapy to the ARTISTIC15 meta-analysis. Given the ability of the meta- Methodology, UCL, London, UK
pelvic lymph nodes, at the investigator’s discretion. analysis to attain power for disease-specific survival, and (A D Cook MSc,
H Pickering PGCert,
Radiotherapy was planned with the patient supine, with based on the observed event rate from external sources,
Prof M K B Parmar DPhil,
empty rectum and comfortably full bladder. Patients the RADICALS team amended the primary outcome of Prof M R Sydes MSc)
could also receive up to 2 years’ hormone therapy (either the RADICALS-RT comparison to FFDM that would Correspondence to:
a luteinising hormone releasing hormone analogue or have greater power at any given time. This change was Prof Matthew R Sydes,
bicalutamide 150 mg once a day) starting before and made with all ethical and regulatory approvals in MRC Clinical Trials Unit at UCL,
London WC1V 6LJ, UK
continuing during and after their postoperative radio­ place, without reference to accumulating comparative
m.sydes@ucl.ac.uk;
therapy, either according to clinical judgment, or if data from RADICALS-RT, and was agreed with the mrcctu.radicals@ucl.ac.uk
participating in RADICALS-HD1 randomly allocated to trial steering committee (which includes independent For the protocol see http://www.
receive either no, 6 months, or 2 years of hormone members, including the chair) and gained favourable radicals-trial.org/media/1128/
therapy. international peer review, through Cancer Research UK. radicals-protocol-version-60-14-
dec-2018.pdf

1396 patients randomised post-prostatectomy

699 allocated to salvage radiotherapy policy 697 allocated to adjuvant radiotherapy policy
228 had PSA progression and reported radiotherapy 648 reported radiotherapy within 1 year
58 had PSA progression and did not report radiotherapy 1 reported radiotherapy after 1 year
413 did not report PSA progression or radiotherapy 48 did not report radiotherapy

Median follow-up was 5·0 years Median follow-up was 4·7 years
33 patients had no data in the last 18 months 54 patients had no data in the last 18 months
and were last seen alive and were last seen alive

699 patients included in analysis 697 patients included in analysis

Figure 1: Trial profile

PSA=prostate-specific antigen.

www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1 3

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Secondary outcomes were survival and disease-specific Comparative data for long-term outcome measures
survival, initiation of non-protocol hormone therapy, remain confidential to the independent data monitoring
treat­
ment toxicity, and patient-reported outcomes. committee and are not reported here.
Freedom from biochemical progression was added as
a secondary outcome measure in 2018 to facilitate Statistical analysis
the ARTISTIC meta-analysis without reference to the The sample size target was originally approximately
accumulating data and with the approval of the oversight 2600 patients recruited over 5·5 years and followed up
committees. The other two trials, RAVES and GETUG- for a further 7 years, to have 80% power to detect an
AFU 17, were both designed with a focus on biochemical improvement from 70% to 75%, or 90% power to detect
progression. an improvement from 80% to 85% in disease-specific
Biochemical progression-free survival (bPFS) was survival. In 2011, the primary outcome of RADICALS-RT
defined as freedom from PSA of 0·4 ng/mL or greater was brought forward to FFDM following a review of the
following postoperative radiotherapy, or PSA of more expected event rate based on external publications.
than 2·0 ng/mL at any time, or clinical progression, or To target an improvement in patients free of distant
initiation of non-protocol hormone therapy, or death from metastases at 10 years from 90% to 95%, with 80% power
any cause. This definition of bPFS was agreed in col­ at a two-sided 5% significance level would require
laboration with the RAVES and GETUG-AFU 17 trial 66 patients with distant metastases events, assuming
teams and registered in PROSPERO with the ARTISTIC still 5·5 years of accrual, a further 7 years of follow-up,
meta-analysis protocol.16 and that 30% of patients would not be assessable
for prostate cancer survival from 5 up to 10 years after
randomisation. This target difference was anticipated to
Salvage Adjuvant All require 1063 patients at an accrual rate of 30 patients
radiotherapy radiotherapy (n=1396)
(n=699) (n=697) per month or 1160 patients at 25 patients per month.
The trial management group continued to project and
Age, years 65 (60–68) 65 (60–68) 65 (60–68)
track combinations of accrual rates and expected time to
PSA at diagnosis, 8·0 7·8 7·9
ng/mL (5·6–11·6) (5·8–11·4) (5·7–11·5)
the target number of events, without reference to any
Gleason score
accumulating interim data.
<7 48 (7%) 48 (7%) 96 (7%)
The other two relevant trials, RAVES and
3 + 4 338 (48%) 349 (50%) 687 (49%)
GETUG-AFU 17, had bPFS as their primary outcome
measure. The RADICALS trial management group
4 + 3 190 (27%) 188 (27%) 378 (27%)
agreed, with sup­port of the independent members of
≥8 123 (18%) 112 (16%) 235 (17%)
the oversight committees, to assess and report on bPFS
Pathological T-stage
before the analysis of RADICALS-RT’s primary outcome
2 176 (25%) 163 (23%) 339 (24%)
measure. This analysis would be timed to coincide
3a 389 (56%) 407 (58%) 796 (57%)
with the planned reporting of the other trials and to
3b 130 (19%) 122 (18%) 252 (18%)
facilitate a timely meta-analysis. We calculated having
4 4 (1%) 5 (1%) 9 (1%)
approximately 80% power to detect a hazard ratio (HR)
Positive margins
of 0·70 if 5-year bPFS was 0·86 in the early salvage
Present 443 (63%) 439 (63%) 882 (63%)
group.
Absent 256 (37%) 258 (37%) 514 (37%)
All analyses were done on an intention-to-treat basis.
Lymph node involvement For time-to-event analysis of bPFS, patients without
Node positive 28 (4%) 38 (5%) 66 (5%) events were censored at the date of their most recent
Node negative 374 (54%) 335 (48%) 709 (51%) PSA measurement and groups were compared with use
No dissection 297 (42%) 322 (46%) 619 (44%) of the log-rank test. The HR is reported as the measure
CAPRA-S score of effect, and analyses are stratified by ran­domisation
Low (0–2) 55 (8%) 58 (8%) 113 (8%) stratification factors. Kaplan-Meier graphs are struc­
Intermediate (3–5) 384 (55%) 382 (55%) 766 (55%) tured in the KMunicate format.17 Toxicity data are
High (6+) 260 (37%) 257 (37%) 517 (37%) divided into events reported as within 2 years after
Country randomisation, and subsequently. Within each period,
UK 573 (82%) 574 (82%) 1147 (82%) the highest grade of event experienced by patients was
Denmark 92 (13%) 95 (14%) 187 (13%) compared between randomised groups using the χ² test.
Canada 28 (4%) 22 (3%) 50 (4%) For patient-reported outcomes, groups were compared
Ireland 6 (1%) 6 (1%) 12 (1%) at 1 year and 5 years with use of analysis of covari­ance,
Data are n (%) or median (IQR). PSA=prostate-specific antigen. CAPRA-S=Cancer of adjusted for baseline score. Stata, version 16.1 was used
the Prostate Risk Assessment post-surgical. for statistical analysis. An independent data monitoring
committee was used. This study is registered with
Table 1: Baseline characteristics
ClinicalTrials.gov, NCT00541047.

4 www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1

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Role of the funding source patients in the adjuvant radiotherapy group and 82 in
The funder of the study had no role in study design, data patients in the salvage radiotherapy group (figure 2A). No
collection, data analysis, data interpretation, or writing of evidence was seen of a difference between the adju­vant
the report. The corresponding author had full access to and salvage groups in terms of bPFS (HR for adjuvant
all the data in the study and had final responsibility for radiotherapy 1·10, 95% CI 0·81–1·49; p=0·56). 5-year
the decision to submit for publication. bPFS was 85% for those in the adjuvant radiotherapy
group and 88% for those in the salvage radiotherapy
Results group.
RADICALS-RT recruited 1396 patients over 9 years Among patients with a bPFS event, 91 (54%) of
between Nov 22, 2007, and Dec 30, 2016, with participants 169 reported initiation of non-protocol hormone therapy
being randomly assigned to an adjuvant radiotherapy (42 [48%] of 87 in the adjuvant group, 49 [60%] of 82 in the
(n=697 [50%]) or salvage radiotherapy policy (n=699 [50%]). salvage group). At 5 years, 7% of patients in the adjuvant
The trial profile is shown in figure 1 (see also appendix group and 8% of patients in the salvage group had See Online for appendix
p 2). Median age was 65 years (IQR 60–68), median PSA initiated non-protocol hormone therapy (HR for adjuvant
at diagnosis was 7·9 ng/mL, and 517 (37%) of 1396 had group 0·88, 95% CI 0·58–1·33; p=0·53; figure 2B).
a Cancer of the Prostate Risk Assessment post-surgical Regarding long-term efficacy outcome measures, at the
(CAPRA-S) score18 of 6 or greater (table 1, appendix pp 3–4). time of analysis, data for the primary outcome measure of
Median PSA at randomisation was undetectable in both
randomised groups. Median follow-up was 4·9 years at
A
the time of data freeze (March 21, 2019).
1·0
Most patients allocated to the adjuvant radiotherapy
policy began treatment, as planned, shortly after ran­ 0·8
Proportion without event

domisation (appendix p 5). 647 (93%) of 697 patients

allocated to the adjuvant radiotherapy group reported 0·6
starting radiotherapy within 6 months at a median of
4·9 months (IQR 4·1–5·7) after prostatectomy. At the 0·4
time of analysis, 228 patients allocated to the salvage
radio­therapy group had started treatment following 0·2
Adjuvant
PSA biochemical progression; 223 (32%) of 699 patients Salvage
0
allocated to the salvage radiotherapy group started 0 1 2 3 4 5 6 7 8
radiotherapy within 5 years after randomisation. The Adjuvant
median PSA measure­ment at the time of starting salvage At risk 697 650 596 470 361 239 154 82 36
Censored 0 35 73 176 266 380 462 531 575
radiotherapy was 0·2 (IQR 0·1–0·3) ng/mL. Among Event 0 12 28 51 70 78 81 84 86
patients allocated to the salvage radiotherapy policy, Salvage
At risk 699 665 601 477 378 263 165 95 42
58 (8%) of 699 met the protocol definition of PSA Censored 0 26 69 175 263 368 459 527 577
biochemical progression during follow-up but did not yet Event 0 8 29 47 58 68 75 77 80
report starting radiotherapy. Most patients who had
radiotherapy received 66 Gy in 30 fractions (n=536 [61%] B
1·0
of 877) or 52·5 Gy in 20 fractions (n=258 [29%] of 877),
with similar proportions in both randomised groups. 0·8
Proportion without event

Most patients received radiotherapy to the prostate bed

only, with radiotherapy additionally to pelvic lymph nodes 0·6
in only 21 (3%) of 649 patients on salvage radiotherapy
and 15 (7%) of 228 patients on adjuvant radiotherapy. 0·4
Of the 649 patients in the adjuvant radiotherapy group
who began radiotherapy, 154 (24%) of 649 also reported 0·2
receiving neo-adjuvant or adjuvant hormone therapy,
90 randomly assigned to 6 months and 45 to 2 years of 0
0 1 2 3 4 5 6 7 8
treatment in RADICALS-HD, and a further 19 reported Time since randomisation (years)
Adjuvant
hormone therapy outside of RADICALS-HD. Of the At risk 697 671 632 511 408 291 200 119 58
228 patients in the salvage radiotherapy group who began Censored 0 22 58 165 259 371 458 536 597
radiotherapy, 61 (27%) of 228 reported receiving neo- HT 0 4 7 21 30 35 39 42 42
Salvage
adjuvant or adjuvant hormone therapy, 33 to 6 months At risk 699 688 646 517 412 305 208 125 62
and 13 to 2 years of treatment in RADICALS-HD, and Censored 0 5 34 148 248 347 442 525 588
HT 0 6 19 34 39 47 49 49 49
15 outside of RADICALS-HD.
Regarding early efficacy outcome measures, 169 bio­ Figure 2: Biochemical progression-free survival (A) and freedom from non-protocol HT (B)
chem­ical progression events were reported—87 events in HT=hormone therapy.

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Early (<2 years) Late (≥2 years)

All Salvage Adjuvant p value All Salvage Adjuvant p value
(n=1372) radiotherapy radiotherapy (n=1220) radiotherapy radiotherapy
(n=696) (n=676) (n=621) (n=599)
Diarrhoea
Grade 1 or 2 372 (27%) 112 (16%) 260 (38%) <0·0001 153 (13%) 50 (8%) 103 (17%) <0·0001
Grade 3 13 (1%) 3 (<1%) 10 (1%) ·· 7 (1%) 2 (<1%) 5 (1%) ··
Grade 4 0 0 0 ·· 1 (<1%) 0 1 (<1%) ··
Proctitis
Grade 1 or 2 196 (14%) 47 (7%) 149 (22%) <0·0001 111 (9%) 34 (5%) 77 (13%) <0·0001
Grade 3 11 (1%) 3 (<1%) 8 (1%) ·· 7 (1%) 1 (<1%) 6 (1%) ··
Grade 4 0 0 0 ·· 0 0 0 ··
Cystitis
Grade 1 or 2 255 (19%) 84 (12%) 171 (25%) <0·0001 122 (10%) 42 (7%) 80 (13%) <0·0005
Grade 3 16 (1%) 5 (1%) 11 (2%) ·· 10 (1%) 4 (1%) 6 (1%) ··
Grade 4 1 (<1%) 0 1 (<1%) ·· 0 0 0 ··
Haematuria
Grade 1 or 2 96 (7%) 25 (4%) 71 (11%) <0·0001 95 (8%) 25 (4%) 70 (12%) <0·0001
Grade 3 22 (2%) 2 (<1%) 20 (3%) ·· 26 (2%) 2 (<1%) 24 (4%) ··
Grade 4 0 0 0 ·· 0 0 0 ··
Urethral stricture
Grade 1 or 2 62 (5%) 21 (3%) 41 (6%) 0·020 55 (5%) 19 (3%) 36 (6%) 0·0025
Grade 3 64 (5%) 27 (4%) 37 (5%) ·· 39 (3%) 13 (2%) 26 (4%) ··
Grade 4 5 (<1%) 3 (<1%) 2 (<1%) ·· 3 (<1%) 3 (<1%) 0 ··
Data are n (%). p values represent adjuvant versus salvage, χ² test. No grade 5 events reported.

Table 2: Radiation Therapy Oncology Group toxicity

RTOG toxicity events were more commonly reported

A B
24
in the group randomised to adjuvant radiotherapy
Salvage
Adjuvant in comparison with the salvage radiotherapy group
(table 2). Most diarrhoea, proctitis, and cystitis events
p=0·0023 p=0·073 p<0·0001 p=0·084
18 were low severity, with grade 3 or 4 events reported for
(397)
(168)
approximately 1% of patients. In the first 2 years after
(510) (406) (162)
(529) (185) (368) randomisation, grade 3–4 haematuria was reported
(493)
Score

12
(507) (177) for 20 (3%) patients in the adjuvant radiotherapy group
and two (<1%) patients in the salvage radiotherapy
(397)
group. Beyond 2 years after randomisation, grade 3–4
6
haematuria was reported for 24 (4%) patients in the
adjuvant radiotherapy group and 2 (<1%) patients in the
salvage radiotherapy group. Grade 3–4 urethral stricture
0
Baseline Year 1 Year 5 Baseline Year 1 Year 5 was also more commonly reported among patients
Time Time in the adjuvant radiotherapy group within 2 years
post-randomisation (39 [6%] patients in the adjuvant
Figure 3: Patient-reported outcome measures for urinary and bowel function
Urinary (A) and faecal incontinence (B). A score of 0 is the best score and 24 is radiotherapy group and 30 [4%] patients in the salvage
the worst. Box plots show median, IQR, and range (excluding outliers). radiotherapy group). Events meeting the serious adverse
event criteria were uncommon, with 46 events reported
FFDM were not sufficiently mature (number of events in total (33 adjuvant, 13 salvage; appendix p 6), only
observed was not yet near the target number of events) three of which were judged by the site investigator to
for comparison of randomised groups. Patients randomly be probably treatment-related.
assigned to the control group (salvage radiotherapy Patient-reported outcome measures for urinary and
group) were noted to have 91% (95% CI 83–95) FFDM at bowel function showed similar results for both random­
9 years. Data for overall survival were similarly immature, ised groups at baseline (appendix p 8), a small but
with 26 (4%) of 699 deaths among the control group significant worsening of symptoms with adjuvant
(salvage radiotherapy group) patients, eight that were radiotherapy 1 year after randomisation (figure 3), but no
attributed by site investigators to prostate cancer. evidence of a difference at later times.

6 www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1

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Discussion as an indication for salvage radiotherapy. A sub­sequent

This initial analysis of RADICALS-RT has not shown any PSA rise, after radiotherapy, or a rise to more than
benefit for adjuvant radiotherapy after radical prosta­ 2 ng/mL at any time, was regarded as biochemical
tectomy. No advantage was seen in biochemical control progression.
after radiotherapy, or in delaying the need for subse­ Advocates of adjuvant radiotherapy might expect any
quent hormone therapy. Although additional follow-up is benefit to be greatest in those patients with locally
required to assess the effect of adjuvant radiotherapy on advanced disease. Recruitment of the 425 patients in
long-term outcome measures, the low metastatic event SWOG 8794, the only trial to report a survival benefit,
rate observed in the control group to date suggests poor was restricted to those with pathological T-stage 3 or 4
scope for improvement in this patient group. Adjuvant or margin-positive disease. RADICALS-RT included
radiotherapy does have adverse effects, with an increased 984 (70%) of 1396 patients with these features, and a
risk both of urinary incontinence and urethral stric­ further 412 (30%) of 1396 patients in which the clinical
tures. These findings strengthen the case for a policy of team was uncertain about the use of postoperative
observation after radical prostatectomy, with early salvage radiotherapy in the absence of these features (appendix
radiotherapy reserved for use only in patients with PSA pp 2–4). The prospective ARTISTIC meta-analysis col­
biochemical progression. Most individuals following laboration has been developed to include all the relevant
such a policy will avoid the need for radio­therapy. randomised trials of postoperative radiotherapy timing.15
The RADICALS-RT design differs from that of previous The meta-analysis will enable subgroup analyses to
trials of adjuvant radiotherapy. In essence, SWOG 87943 investigate whether any effect of adjuvant radiotherapy is
and EORTC 229114,5 each compared adjuvant radiotherapy consistent across risk groups.
to observation alone. Salvage radiotherapy was not man­ We do not yet have good quality evidence concerning
dated for PSA biochemical progression in the observation the effect of postoperative radiotherapy timing on longer-
group, and when it was given, it was typically given term outcomes such as FFDM. The ARO 96-02 trial
late. For example, in the SWOG trial, only 39 (18%) of (n=307) had only 47 metastatic events at the time of the
211 patients received salvage radiotherapy for PSA latest update, with 22 in the control group and 25 in the
biochemical progression, and the median PSA at the time adjuvant radiotherapy group (p=0·53).6 The Finnish
of salvage radiotherapy was 0·75 ng/mL. By contrast, the Radiation Oncology Group trial (n=250) had just six
median PSA amount in RADICALS-RT at the time of metastatic events.7 Although bPFS is not a surrogate for
salvage treatment was 0·2 ng/mL. It is possible that the FFDM, typically, trials of prostate radiotherapy show a
late use, if at all, of timely salvage radiotherapy might greater treatment effect in terms of bPFS than for longer-
have contributed to the overall survival benefit reported term outcomes. In the MRC PR07 trial, the point estimate
with adjuvant radiotherapy in the SWOG trial. These of the HR for radiotherapy effect was 0·31 for bPFS, and
older trials are therefore of limited use in determining the 0·70 for overall survival.19 In RADICALS-RT, if we had
optimum timing of postoperative radiotherapy. observed a significant bPFS benefit, it would not have
The ARO 96-02 trial6 and the Finnish Radiation been safe to conclude that there will be an FFDM benefit.
Oncology Group trial7 did include timely salvage radio­ However, the observed absence of benefit in terms of
therapy in the control group, but were relatively small bPFS makes it unlikely that a benefit in FFDM will
trials, with a combined total of 557 patients. Both trials emerge. Taken together with the absence of demon­
found that adjuvant radiotherapy reduced the risk of strable benefit in RADICALS-RT with regard to time to
biochemical progression. However, PSA biochemical subsequent hormone therapy, the weight of current
progression at any time was regarded as an event, even in evidence does not suggest that adjuvant radiotherapy
patients who subsequently went on to receive successful confers a worthwhile long-term benefit in comparison
salvage radio­ therapy. In other words, the trigger for with a salvage radiotherapy policy. With continued
salvage radio­therapy also counted as an event. Therefore, follow-up of all trials, the ARTISTIC meta-analysis will
a benefit in biochemical progression defined by this be powered to report on overall survival.
measure simply shows that radiotherapy has activity, but RADICALS-RT has several strengths. It is the largest
does not shed any light on its optimal timing. Indeed, this randomised controlled trial of adjuvant radiotherapy after
point is well illustrated by the EORTC 22911 trial, which radical prostatectomy, it mandates salvage radiotherapy
first showed a substantial benefit for adjuvant radiotherapy in the control group, and is powered to study—in due
in bPFS (HR 0·48, 95% CI 0·37–0·62), but no benefit in course—the long-term outcome measure of FFDM. The
overall survival (HR 1·09, 0·67–1·79). By contrast, the patient population, recruited primarily from Canada,
definition of biochemical progression in RADICALS-RT Denmark, and the UK, is representative of men under­
was designed to be a fairer comparison between the going radical prostatectomy in high-income countries.
two groups, by focusing on PSA biochemical progression Compliance with allocated treatment and follow-up was
after radiotherapy. In RADICALS-RT, a small initial PSA high and was consistent across both groups. Outcome
rise in patients in the salvage radiotherapy group was measures included not only physician-assessed toxicity,
regarded not as biochemical progression, but rather only but also patient-reported functional outcomes.

www.thelancet.com Published online September 28, 2020 https://doi.org/10.1016/S0140-6736(20)31553-1 7

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RADICALS-RT also has some limitations. Although discrepancies from the study as planned (and, if relevant, registered)
recruitment started in 2007, follow-up is at this time have been explained.
insufficient to reliably report long-term outcomes such Declaration of interests
as FFDM. During the period since RADICALS-RT CCP reports grants, personal fees, and other from Bayer, other from
AAA, and personal fees from Janssen, outside the submitted work.
started recruitment, new evidence has suggested that NWC reports personal fees from Janssen, during the conduct of the
men receiving salvage radiotherapy benefit from the study; and personal fees from Janssen, outside the submitted work.
addition of hormone therapy: RTOG 9601 showed an CC reports grants from Canadian Cancer Trials Group, during the
advantage in overall survival for 2 years of bicalutamide20 conduct of the study; personal fees from Bayer, grants from
AstraZeneca, and personal fees from AbbVie, Janssen, and Astellas,
and GETUG-16 showed an advantage for 6 months of outside the submitted work. HPa reports personal fees from Janssen,
goserelin in progression-free survival.21,22 Around 30% of Astellas, AstraZeneca, Ferring, and Ipsen, outside the submitted work.
patients in RADICALS-RT reported receiving hormone FS reports grants, personal fees, and non-financial support from
therapy with their postoperative radiotherapy. Although Astellas, Amgen, Janssen, Bayer, Sanofi, Pfizer, AstraZeneca, and
Myovant, outside the submitted work. HL reports personal fees and
greater use of hormone therapy might have improved non-financial support from Astellas Phama, Bayer, Janssen, and Sanofi
outcomes, there is no evidence that it would have had a Aventis, and personal fees from Roche, outside the submitted work.
differential effect on the two arms of the trial. Similarly, AZ reports other fees from Bayer, personal fees from Pfizer, Janssen,
evidence from the RTOG SPPORT trial23 suggests a Astellas, and EUSA Pharma, and grants from Sanofi, outside the
submitted work. MKBP reports grants and non-financial support from
benefit to treating not just the prostate bed, but also the Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the
pelvic lymph nodes in men receiving salvage radio­ submitted work. MRS reports grants and non-financial support from
therapy. This option was permitted in RADICALS-RT, Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, personal fees
but more than 95% of patients received treatment to the from Eli Lilly, and grants, personal fees, and non-financial support from
Janssen, outside the submitted work. All other authors declare no
prostate bed alone. Once again, there is no evidence competing interests.
that pelvic nodal radiotherapy would have a differential
Data sharing
effect in the adjuvant or salvage setting. Advances in The dataset and technical appendices are available upon request as per
treatment, such as these, provide another argument in the controlled access approach of the MRC Clinical Trials Unit at UCL.
favour of a salvage radiotherapy policy. Given that Please contact the corresponding author for more information.
patients might receive salvage radio­therapy years after Acknowledgements
their prostatectomy, they could benefit from new We recognise the efforts of all trial team members at the trials units and
hospitals who have supported and engaged with RADICALS. A list of
knowledge not available in the immediate postoperative
investigators and oversight committee members is given in the appendix
period. (pp 9–15). We thank Tim Morris for putting the time-to-event graphs
The prospective ARTISTIC meta-analysis collaboration into KMunicate format. Grant funding in the UK was provided by the
has been developed to include all the relevant randomised Clinical Trials Advisory Award Committee on behalf of Cancer Research
UK (UK/C7829/A6381). Funding in Canada was provided by the
trials of postoperative radiotherapy timing, and, with Canadian Cancer Society (704970). The trial was further supported at the
continued follow-up of all trials, will be powered to report MRC Clinical Trials Unit at UCL by a core grant from the MRC, now
on FFDM and overall survival. The meta-analysis will part of the UK Research and Innovation (MC_UU_12023/28). UK sites
also enable subgroup analyses to investigate whether were part of the Health Research Clinical Research Network. This paper
represents independent research part-funded by the National Institute
any effect of adjuvant radiotherapy is consistent across for Health Research (NIHR) Biomedical Research Centre at the Royal
CAPRA-S scores. Marsden NHS Foundation Trust and the Institute of Cancer Research.
The RADICALS-RT trial has not shown any benefit for The views expressed are those of the authors and not necessarily those
adjuvant radiotherapy in comparison to a policy of salvage of the NHS or the NIHR. Matthew R Sydes and Mahesh K B Parmar
are funded by the MRC. We thank all of the research staff who worked
radiotherapy for PSA biochemical progression; however, with the investigators and each site. Finally, and most importantly,
adjuvant radiotherapy does increase the risk of urinary we recognise and thank all of the participants of the trial and the
and bowel morbidity. In the absence of any reliable families and friends who supported them. Clinical trials only happen
evidence that adjuvant radiotherapy does more good because people choose to join them.
than harm, observation with salvage treatment for PSA References
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